1. Technical Field
The present disclosure relates to a process, method and/or system for preparing polymer coated nanoparticles/ultrafine particles and the coated nanoparticles/ultrafine particles produced thereby. More particularly, the present disclosure relates to a process, method and/or system for preparing polymer-coated nanoparticles/ultrafine particles using a supercritical fluid, e.g., supercritical carbon dioxide, as an antisolvent in to which a solution or system that includes the polymer and an organic solvent is introduced. The nanoparticles/ultrafine particles are typically suspended in the organic solvent. Processing parameters for optimizing and/or enhancing the efficacy and/or efficiency of the disclosed coating process, method and/or system and for controlling the coating and/or agglomeration of coated particles are also described.
2. Background of Related Art
The rapid development of nanotechnology and nanomaterials has led to a need for nanoparticle surface modification for a variety of applications. The surface can be tailored to specific physical, optical, electronic, chemical and biomedical properties by coating a thin film of material on the surface of the nanoparticles. Conventional nanoparticle coating methods include dry and wet approaches. Dry methods include: (a) physical vapor deposition [Y. Zhang, Q. Zhang, Y. Li, N. Wang, J. Zhu, Coating of carbon nanotubes with tungsten by physical vapor deposition, Solid State Commun. 115 (2000) 51], (b) plasma treatment [D. Shi, S. X. Wang, W. J. Ooij, L. M. Wang, J. G. Zhao, Z. Yu, Uniform deposition of ultrathin polymer films on the surfaces of Al2O3 nanoparticles by a plasma treatment, Appl. Phys. Lett. 78 (2001) 1243; D. Vollath, D. V. Szabó, Coated nanoparticles: a new way to improved nanocomposites, J. Nanoparticle Res. 1 (1999) 235], (c) chemical vapor deposition [O. Takeo, N. Koichi, S. Katsuaki, Formation of carbon nanocapsules with SiC nanoparticles prepared by polymer pyrolysis, J. Mater. Chem. 8 (1998) 1323], and (d) pyrolysis of polymeric or non-polymeric organic materials for in situ precipitation of nanoparticles within a matrix [V. M. Sglavo, R. Dal Maschio, G. D. Soraru, A. Bellosi, Fabrication and characterization of polymer-derived silicon nitride oxide Zirconia (Si2N2O—ZrO2) nanocomposite ceramics, J. Mater Sci. 28 (1993) 6437]. Wet methods for coating nanoparticles include: (a) sol-gel processes and (b) emulsification and solvent evaporation techniques [H. Cohen, R. J. Levy, J. Gao, V. Kausaev, S. Sosnowski, S. Slomkowski, G. Golomb, Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles, Gene Ther. 7 (2000) 1896; J. S. Hrkach, M. T. Peracchia, A. Domb, N. Lotan, R. Langer, Nanotechnology for biomaterials engineering: structural characterization of amphiphilic polymeric nanoparticles by 1H NMR spectroscopy, Biomaterials 18 (1997) 27; D. Wang, D. R. Robinson, G. S. Kwon, J. Samuel, Encapsulation of plasmid DNA in biodegradable poly(D,L-lactic-co-glycolic acid) microspheres as a novel approach for immunogene delivery, J. Control. Rel. 57 (1999) 9].
The coating or encapsulation of nanoparticles has been found to be of particular interest for the controlled release of drugs, genes, and other bioactive agents. Controlled release systems provide the benefits of protection from rapid degradation, targeting delivery, control of the release rate, and prolonged duration of bioactive agents.
Leroux et al. studied the surface modification of nanoparticles of poly D,L-lactic acid (D,L-PLA) loaded with drugs to improve site-specific drug delivery. [See, J. C. Leroux, E. Allémann, F. D. Jaeghere, E. Doelker, R. Gumy, Biodegradable nanoparticles—from sustained release formulations to improved site specific drug delivery, J. Control. Rel. 39 (1996) 339]. The drug delivery system was prepared using the emulsion method. Results indicated that drug loaded nanoparticles of D,L-PLA, which were coated with polyethylene glycol (PEG), provided protection from uptake by human monocytes. The findings revealed that surface modified nanoparticles with PEG could temporarily avoid the mono-nuclear phagocyte system and substantially prolong the circulation time of the nanoparticles.
Bertucco et al. did a preliminary study of particle encapsulation by polymer using a GAS process. In their study, particles of KCl were suspended in a solution of polymers (hydroxypropyl methylcellulose phthalate, Eudragit® E 100, ethylcellulose) in various organic solvents (toluene, acetone, 1,4-dioxane, ethylacetate). Compressed CO2 was introduced into a high-pressure vessel, in which the suspension was charged. The compressed CO2 was dissolved in the organic solution, leading to the loss of solvent strength of the organic solvent. As a result, the polymer precipitated out and deposited on the surface of suspended KCl particles. [Bertucco et al., “Drugs encapsulation using a compressed gas antisolvent technique,” The Fourth Italian Conference on Supercritical Fluids and their Application, E. Reverchon (Ed.), September 7-10, Capri, 1997, 327-334.]
Cohen et al. prepared a sustained gene delivery system of DNA encapsulated in polymeric nanoparticles using a double emulsion approach. [See, Cohen et al., Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles, Gene Ther. 7 (2000) 1896]. In their research, the gene delivery system was found to offer increased resistance to nuclease degradation since the polymeric coating provides protection from serum nuclease. The activity of plasmid DNA administration was found to be in the sustained duration mode. The gene delivery system is a potential formulation for the application of gene therapy.
The emulsion techniques used above are associated with the following four steps: (a) preparing the solution of polymer and bioactive agent in an organic solvent, (b) dispersing the solution in another phase under vigorous stirring, (c) stabilizing under certain temperature and pH conditions, and (d) evaporating the organic solvent. However, during the emulsion preparation, the organic solvent and the strong shearing force, temperature, pH, and the interface between the oil and water phases may affect and/or alter the structure of the bioactive agents. In addition, these processes require large amount of organic solvents, surfactants, and other additives, leading to volatile organic compound (VOC) emissions and other waste streams. Other drawbacks include low encapsulation efficiency and further processing of the products such as down-stream drying, milling and sieving, which are usually necessary. In addition, residual toxic solvent in the end products, temperature and pH requirements, and strong shear forces are big challenges for maintaining the fragile protein structure in the encapsulation of pharmaceutical ingredients.
There are a number of prior art publications dealing with particle coating or encapsulation using supercritical carbon dioxide [“SC CO2”]. For example, Kim et al. reported the microencapsulation of naproxen using rapid expansion of supercritical solutions (RESS). [See, J. H. Kim, T. E. Paxton, D. L. Tamasko, Microencapsulation of naprozen using rapid expansion of supercritical solutions, Biotechnol. Prog. 12 (1996) 650]. The RESS process was also used to coat/encapsulate particles by Mishima et al. [See, K. Mishima, K. Matsuyama, D. Tanabe, S. Yamauchi, T. J. Young, K. P. Johnston, Microencapsulation of proteins by rapid expansion of supercritical solution with a nonsolvent, AIChE J. 46 (4) (2000) 857-865]. In the RESS coating process, the material to be coated and the coating material (polymer) are both dissolved in SC CO2 with or without a cosolvent. The solution is then released from a nozzle (de-pressurized), generating microparticles with a polymer coating on the surface. In RESS, the rapid de-pressurization of the supercritical solution causes a substantial lowering of the solvent power of CO2 leading to very high supersaturation of solute, precipitation, nucleation and particle growth. However, the application of the RESS process is severely limited by the fact that polymers, in general, have very limited solubility in SC CO2 at temperatures below 80° C. Also, the operating pressure in RESS is usually above 200 bars so that the process is less attractive economically.
Tsutsumi et al. used a combination of the RESS process and a fluidized bed for coating particles. [See, A. Tsutsumi, S. Nakamoto, T. Mineo, K. Yoshida, A novel fluidized-bed coating of fine particles by rapid expansion of supercritical fluid solutions, Powder Technol. 85 (1995) 275]. In their research, a solution of coating material in SC CO2 (rather than in an organic solvent) is sprayed into the fluidized bed of particles to be coated. However, particles less than 30-50 μm fall into Geldart's Group C particle classification and are very difficult to fluidize. Hence, this method cannot be used to coat ultrafine particles.
Pessey et al. also demonstrated particle coating using a supercritical fluid process. [See, V. Pessey, D. Mateos, F. Weill, F. Cansell, J. Etoumeau, B. Chevalier, SmCo5/Cu particles elaboration using a supercritical fluid process, J. Alloys Compounds 323 (2001) 412]. Their research involved the thermal decomposition of an organic precursor and the deposition of copper onto the surface of core particles in SC CO2 under conditions of temperature up to 200° C. and pressure up to 190 MPa. However, their methods are less attractive from the point of view of safety and cost and probably cannot be applied to the pharmaceutical industry since high temperature could adversely effect or even destroy most drug powders.
Tom and Debenedetti investigated a SC CO2 process for the formation of drug loaded microspheres for controlled drug release. In this work, a model system of biopolymer PLA and pyrene was chosen for the composite powder formation study. PLA and pyrene were dissolved in SC CO2 with acetone as a cosolvent in two different units. The two resulting supercritical solutions were mixed and were pumped to an expansion device (orifices or capillaries, 25-50 μm). When the solution flowed through the expansion device, it underwent a rapid decompression, resulting in co-precipitation of the solutes. It was found that the pyrene was uniformly incorporated into the produced polymer microspheres. [See, Tom et al., Precipitation of poly (L-lactic acid) and composite poly (L-lactic acid)-pyrene particles by rapid expansion of supercritical solutions, J. Supercrit. Fluids, 7, 1994, 9-29.]
Recently, Wang et al. used a modified RESS process of extraction and precipitation to coat particles with polymer. [See, Wang et al., Extraction and precipitation particle coating using supercritical CO2, Powder Technology 127 (2002) 32-44.] The coating polymer and particles to be coated (host particles) were placed in two different high-pressure vessels, respectively. The coating polymer was first extracted by SC CO2. The resulting supercritical polymer solution was then introduced into the host particle vessel. By adjusting the temperature and pressure, the polymer solubility in SC CO2 was lowered and nucleation and precipitation of polymer took place on the surface of the host particles and a fairly uniform polymer coating was formed. However, potential application of RESS for particle coating or encapsulation is limited because the solubility of polymers in SC CO2 is generally very poor. [See, O'Neill et al., Solubility of Homopolymers and Copolymers in Carbon Dioxide, Ind. Eng. Chem. Res. 37 (1998) 3067-3079.] As an alternative, antisolvent processes (GAS/SAS/ASES/SEDS) for drug delivery system design have attracted attention because of their flexibility in choosing a suitable solvent which is miscible with SC CO2.
The use of SC CO2 as an antisolvent (SAS process), however, can usually be performed at a pressure lower than 10 MPa and at a temperature just above the critical temperature (304.1° K). Also the SAS process is quite flexible in terms of solvent choice. Thus, the synthesis of ultrafine particles using SAS has been reported in a number of studies [E. Reverchon, G. Della Porta, I. De Rosa, P. Subra, D. Letourneur, Supercritical antisolvent micronization of some biopolymers, J. Supercrit. Fluids 18 (2000) 239; D. J. Dixon, K. P. Johnston, R. A. Bodmeier, Polymeric materials formed by precipitation with a compressed fluid antisolvent, AIChE J. 39 (1993) 127; R. Falk, T. W. Randolph, J. D. Meyer, R. M. Kelly, M. C. Manning, Controlled release of ionic compounds from poly (L-lactide) microspheres produced by precipitation with a compressed antisolvent, J. Control. Release 44 (1997) 77; T. J. Young, K. P. Johnston, K. Mishima, H. Tanaka, Encapsulation of lysozyme in a biodegradable polymer by precipitation with a vapor-over-liquid antisolvent, J. Pharmaceut. Sci. 88 (1999) 640].
Falk et al. investigated the production of composite microspheres by the SAS process. [See, Falk et al., Controlled release of ionic compounds from poly (L-lactide) microspheres produced by precipitation with a compressed antisolvent, J. Control. Release 44 (1997) 77]. In their study, drugs of gentamycin, naloxone and naltrexone and PLA were dissolved in methylene chloride using the hydrophobic ion-pairing (HIP) complexation method, which improved the solubility of the drugs considerably, to make a homogeneous solution. The prepared solutions were sprayed into SC CO2 through an ultrasonic nozzle vibrating at 120 kHz. The drug loaded microspheres (0.2-1.0 μm) formed due to the co-precipitation of the drugs and the PLA. Drug release tests showed that gentamycin was successfully incorporated into a PLA matrix, exhibiting diffusion controlled drug release. However, naltrexone and rifampin were found to be poorly incorporated because these two drugs were more lipophilic and somewhat soluble in SC CO2, resulting in drug surface bonding on the microspheres. Recently, Young et al. investigated the encapsulation of lysozyme with a biodegradable polymer by precipitation with a vapor-over-liquid antisolvent, which is a modified precipitation with a compressed antisolvent process. [See, Young et al., Encapsulation of lysozyme in a biodegradable polymer by precipitation with a vapor-over-liquid antisolvent, J. Pharmaceut. Sci. 88 (1999) 640]. In their research, the vapor-over-liquid antisolvent coating process was used to encapsulate 1-10 μm lysozyme particles.
Drug loaded microspheres can be produced by alternative techniques, e.g., phase separation, spray-drying, freeze-drying, and interfacial polymerization techniques. All of these methods involve the dissolution of the polymer and the drug in an organic solvent, dispersion of the solution under a strong force, and stabilization under certain temperature and pH conditions. However, as was the case for emulsion techniques, problems of residual organic solvent in the final product and low encapsulation of drugs due to partitioning of the pharmaceutical components between two immiscible liquid phases are frequently encountered. Moreover, harsh conditions, such as temperatures, pH conditions and strong shear forces, may denature some bio-active agents. Also, extensive downstream processing is usually required when using these conventional methods.
Bleich and Müller have studied drug-loaded particle formation using an ASES process. PLA was used as the carrier and several different drugs, such as hyoscine butylbromide, indomethacin, piroxicam and thymopentin, were selected as model drugs. The drugs and PLA were dissolved in methylene chloride and the solution was atomized into SC CO2 through a 400 μm nozzle at a flow rate of 6 ml/min. The solvation of SC CO2 in the organic solvent resulted in the formation of drug loaded microparticles. It was found that, with decreasing polarity of the incorporated drug, drug loading was lowered as a result of an increase in extraction by SC CO2, with the organic solvent acting as a cosolvent. Polar drugs, such as proteins and peptides, were successfully encapsulated by the ASES process, whereas non-polar drugs failed to be encapsulated and were completely extracted by the SC CO2 and the organic solvent. [Bleich et al., Production of drug loaded microparticles by the use of supercritical gases with the aerosol solvent extraction system (ASES) process, J. Microencapsulation, 13, 1996, 131-139.]
Elvassore et al. studied the formation of protein loaded polymeric microcapsules in the SAS process. A model system of insulin and PLA was dissolved in a mixture of DMSO and dichloromethane. The prepared solution was then sprayed into SC CO2 through a 50 μm fused silica nozzle. The results showed that insulin-loaded microspheres with particle size from 0.5 to 2 μm were produced and the incorporation efficiency was as high as 80%. [Elvassore et al., Production of protein-loaded polymeric microcapsules by compressed CO2 in a mixed solvent, Ind. Eng. Chem. Res., 40, 2001, 795-800.]
Ghaderi et al. studied the formation of microparticles with hydrocortisone loaded in DL-PLA polymer using a combination of SC N2 and CO2 as the antisolvent in a SEDS process. It was shown that microparticles of size less than 10 μm were produced. Hydrocortisone was successfully entrapped in DL-PLA microparticles with a loading efficiency up to 22%. The combination of SC N2 and CO2 was found to facilitate a more efficient dispersion of the polymer solutions than SC CO2 alone. [Ghaderi et al., A new method for preparing biodegradable microparticles and entrapment of hydrocortisone in D,L-PLG microparticles using supercritical fluids, European J. of Pharm. Sci., 10, 2000, 1-9.]
More recently, Tu et al. attempted the microencapsulation of para-hydroxybenzoic acid (β-HBA) and lysozyme with PLA in an ASES process. The drug solution, polymer solution and SC CO2 were delivered through a specially designed coaxial multiple nozzle. Higher loading efficiency of 15.6% was achieved for lysozyme encapsulation, while the β-HBA was poorly encapsulated with an efficiency of 9.2%. [Tu et al., Micronisation and encapsulation of pharmaceuticals using a carbon dioxide antisolvent, Powder Technol. 126, 2002, 134-149.]
Most of the reported research on the formation of drug loaded microspheres for controlled drug release has focused on the co-precipitation of the solute of interest (drug) and the carrier polymer using an antisolvent process. However, since a SAS co-precipitation process requires the dissolution of both the drug and the polymer in a solvent, this creates a challenge for proteins since many proteins are insoluble in organic solvents. Also, many organic solvents can denature the protein's bioactivity. Moreover, the co-precipitation of two different solutes is difficult to achieve except when the two solutes have similar thermodynamic properties and undergo similar precipitation pathways.
Thus, despite efforts to date, a need remains for effective and reliable systems and/or methods for coating and/or encapsulating nanoparticles and other ultrafine particles. In addition, a need remains for effective and reliable systems and/or methods for coating and/or encapsulating nanoparticles and other ultrafine particles, while controlling agglomeration levels. Moreover, an ability to optimize operating conditions and/or operating parameters in implementation of SAS coating processes is highly desirable. These and other objectives are met by the systems and methods disclosed herein.